azacitidine and enasidenib in treating patients with idh2-mutant myelodysplastic syndrome

Conditions: Acute Myeloid Leukemia; Blasts 20-30 Percent of Bone Marrow Nucleated Cells; Chronic Myelomonocytic Leukemia; IDH2 Gene Mutation; Myelodysplastic Syndrome With Excess Blasts; Recurrent High Risk Myelodysplastic Syndrome; Refractory High Risk Myelodysplastic Syndrome

Summary: this phase ii trial studies the side effects and how well azacitidine and enasidenib work in treating patients with idh2-mutant myelodysplastic syndrome. azacitidine and enasidenib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

primary objectives: i. to determine the safety and tolerability of enasidenib alone, and enasidenib in combination with azacitidine (aza), for patients with isocitrate dehydrogenase 2 (idh2) mutated myelodysplastic syndrome (mds). ii. to assess the efficacy of the combination of enasidenib + azacitidine in hypomethylating agent (hma) naive subjects with idh2-mutated mds, and to assess the efficacy of enasidenib single-agent in subjects with idh2-mutated mds who are relapsed/refractory to hma therapy. secondary objectives: i. to evaluate molecular and cellular markers that may be predictive of antitumor activity and/or resistance including evaluation of idh2 variant allele fraction (vaf) levels during treatment and presence of co-occurring mutations. ii. to assess overall survival, event-free survival and duration of response of enasidenib alone, and enasidenib in combination with azacitidine. exploratory objectives: i. to assess changes in cellular differentiation and changes in deoxyribonucleic acid (dna) methylation profiles in idh2-mutated mds treated with enasidenib alone and with enasidenib + azacitidine. ii. to evaluate quality of life (qol) using an mds-specific measure. outline: patients are assigned to 1 of 2 arms. arm i: patients who are hma-naive receive enasidenib orally (po) once daily (qd) on days 1-28 and azacitidine intravenously (iv) oveer 30-60 minutes or subcutaneously (sc) on days 1-7. cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. arm ii: patients relapsed and/or refractory to hma therapy receive enasidenib po qd on days 1-28. cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. after completion of study treatment, patients are followed up every 3 months for up to 3 years.

Eligibility criteria:
inclusion criteria: * signed, informed consent must be obtained prior to any study specific procedures * subjects with a histologically confirmed diagnosis of mds, including both mds and refractory anemia with excess blasts in transformation (raeb-t) (acute myeloid leukemia \[aml\] with 20-30% blasts and multilineage dysplasia by french-american-british \[fab\] criteria) by world health organization (who), and chronic myelomonocytic leukemia (cmml) are eligible * subjects must have an idh2 gene mutation (idh2-r140 or r172) as determined by local laboratory result * (arm a only): subject must be hypomethylating agent naive (i.e. prior azacitidine, decitabine, sgi-110 is exclusionary). receipt of other mds-directed therapy such as lenalidomide is allowed * (arm a only): subjects with high-risk mds (i.e. international prostate symptom score \[ipss\] intermediate-2 or high-risk; or revised \[r\]-ipss high or very-high risk). patients with intermediate-1 risk by ipss or intermediate risk by r-ipss with high-risk molecular features including tp53, asxl1, ezh2, and/or runx1 mutations are also eligible * (arm b only): subject must be relapsed or refractory to prior hypomethylating agent therapy, defined as prior receipt of 6 cycles of hma therapy with failure to attain a response, or relapse after prior response to hma therapy * eastern cooperative oncology group (ecog) performance status of 0-2 * serum bilirubin =\< 2 x the upper limit of normal (uln) (except for patients with gilbert's disease) * alanine aminotransferase (alt) and/or aspartate aminotransferase (ast) =\< 3 x the laboratory uln * serum creatinine =\< 2 x the uln * able to understand and voluntarily sign a written informed consent, and willing and able to comply with protocol requirements * resolution of all clinically significant treatment-related, non-hematological toxicities, except alopecia, from any previous cancer therapy to =\< grade 1 prior to the first dose of study treatment * female patients of childbearing potential must have a negative serum or urine pregnancy test within 7 days of the first dose of study drug and agree to use dual methods of contraception during the study and for a minimum of 3 months following the last dose of study drug. post-menopausal females (\> 45 years old and without menses for \> 1 year) and surgically sterilized females are exempt from these requirements. male patients must use an effective barrier method of contraception during the study and for a minimum of 3 months following the last dose of study drug if sexually active with a female of childbearing potential exclusion criteria: * any prior or coexisting medical condition that in the investigator's judgment will substantially increase the risk associated with the subject's participation in the study * subject has received a prior targeted idh2 inhibitor * psychiatric disorders or altered mental status precluding understanding of the informed consent process and/or completion of the necessary study procedures * active uncontrolled infection at study enrollment including known diagnosis of human immunodeficiency virus or chronic active hepatitis b or c infection * clinically significant gastrointestinal conditions or disorders that may interfere with study drug absorption, including prior gastrectomy * patients with known active central nervous system (cns) disease, including leptomeningeal involvement * impaired cardiac function, uncontrolled cardiac arrhythmia, or clinically significant cardiac disease including the following: a) new york heart association grade iii or iv congestive heart failure, b) myocardial infarction within the last 6 months * subjects with a corrected qt (qtc) \> 480 ms (qtc \> 510 msec for subjects with a bundle branch block at baseline * nursing or pregnant women * subjects with known hypersensitivity to study drugs or their excipients